As we endeavor to understand the mechanisms and treatment avenues for drug seeking, it is crucial to address unique populations. The developing brain responds differently to drugs of abuse such as stimulants, with a particular window of vulnerability for addiction in adolescence. Extinction of drug-seeking behavior is an integral part of drug addiction treatment, and recently we reported that adolescents are more resistant to extinction relative to adults. Importantly, adolescence also represents a critical period of development when intervention could prevent a lifetime of recurring drug addiction. Recently, research has converged on the ideas that, 1) adolescents are a vulnerable population for drug addiction and display delayed extinction of drug seeking behaviors, 2) extinction and relapse of drug-seeking are mediated through motivational conditioning circuitries, 3) the dopaminergic receptor microcircuitry within the prefrontal cortex (PFC) mediates motivational conditioning, and 4) the adolescent dopamine receptor profile within the PFC is unique. The proposed experiments will build on our recent observation that the D1 dopamine receptor is transiently overproduced on PFC outputs to the nucleus accumbens during adolescence. This application applies these findings to a working hypothesis that may lead to novel treatment strategies targeted to adolescents. These studies serve as a foundation for a crucial line of research into the treatment of adolescent drug addiction, focusing on the extinction of drug-seeking behavior. PUBLIC HEALTH RELEVANCE: Adolescence represents a unique stage of cortical development which results in a particular vulnerability to drug addiction. Heightened responsiveness to drug- associated cues, and diminished ability to respond to less-potent stimuli, render adolescents resistant to extinction of drug-seeking. Therefore, treatment of drug addiction during this critical period of brain development will require distinct strategies from those used for adults, such as cortically-targeted pharmacologic intervention.